ProjectSummary Alcoholandcannabisarethemostcommonlyabuseddrugsandtheyareoftenusedincombination,especially byadolescents.Previousworkhasrevealedthatthefrequentuseofeitherdrugaloneisassociatedwith cognitiveimpairments,includinglossofmemoryfunction,impulsivity,poordecisionmaking,andlackof behavioralflexibility.Thesecognitiveproblems,whichlikelycontributetothepersistenceofdrugaddictionand poortreatmentoutcomes,maybeheightenedinthosewhousebothdrugsincombination.Metabolic dysfunctionisalsoseenindrugabusersandthemechanismsunderlyingtheseeffectsmaycontributetothose thatunderliedrug-inducedcognitiveimpairment.However,thepotentiallysharedmechanismsfordrug-induced metabolicandcognitivedysfunctionhavebeenlargelyunexplored.Here,weusearatmodelofadolescence toinvestigatetheco-useofalcoholand?9-tetrahydrocannibinol(THC),theprimarypsychoactivedrugin cannabis,andtheroleoftheAkt-GSK3?signalingpathwayindrug-inducedchangesinmetabolicactivity, synapticplasticityandbehavioralflexibility.Ourpreliminarydatashowthatadolescentratswhodrank moderatelevelsofalcoholandwereexposedtosyntheticTHC(dronabinol),eithervias.c.injectionororalself- administration,hadsignificantchangesinglucosemetabolismandimpairedsynapticplasticityintheprefrontal cortex(PFC)thatwerenotobservedinratsexposedtoeitherdrugalone.Accordingly,wehypothesizedthat co-useofalcoholandTHCcausesdysregulationoftheAkt-GSK3?signalingpathwayinthemediobasal hypothalamus,whichplaysacriticalroleininsulin-mediatedmetabolism,andinthePFC,whichiscriticalfor normalcognition.Wewilltestthishypothesisinbothmaleandfemaleratsbyidentifyingtheuniqueimpactof adolescentalcoholandTHCco-useon(1)Akt-GSK3?signalinginresponsetometabolicchallengein adulthood,(2)operantbehaviortestsofbehavioralflexibility,and(3)highfrequencystimulation-induced synapticplasticityinthePFC.Weexpectthatourresultswillprovidenewinsightsintohowmechanismsof metabolicandsynapticsignalingareintegratedtocontrolcognition,howcombineduseofalcoholandTHC influencethedevelopingbraintoproducelongtermnegativeoutcomes,andhowthesemechanismsare differentlyregulatedtoproducesexdifferencesintheeffectsofalcoholandTHCco-use.Thesuccessful completionofthisresearchprojectwillshapeourfutureplansforacollaborativeresearchprogramthatis focusedonidentifyingaspecifichypothalamic-corticolimbiccircuitrythatisalteredbyalcoholandTHC exposure.Ourlong-termgoalistoelucidatehowthiscircuitrymediatesnormalenergymetabolismand cognitionandhowtheeffectsofadolescentalcoholandTHCco-usemaybeheightenedcomparedtodrug exposureinadulthood.